- Single-nucleus multiome of BA9 from seven MDD and eight controls mapped gene expression and chromatin accessibility across 20 distinct cell clusters.
- Cell-type-specific dysregulation concentrated in excitatory layer 5 and 6, Pvalb inhibitory neurons, glia and vascular cells affecting synaptic, neurotransmission and myelination pathways.
- Glucocorticoid-responsive transcription factors NR3C1 and NR3C2 show conserved regulatory networks implicating stress signalling in MDD pathophysiology.
Int J Neuropsychopharmacol. 2026 Aug 22:pyag045. doi: 10.1093/ijnp/pyag045. Online ahead of print.
ABSTRACT
OBJECTIVE: Major Depressive Disorder (MDD) is a leading global cause of disability, marked by persistent mood disturbances, cognitive deficits, and changes in prefrontal cortex neural circuitry. In this study, we aimed to define cell-type-specific molecular and regulatory mechanisms underlying MDD by mapping gene-expression and chromatin-accessibility changes in the dorsolateral PFC (dlPFC).
METHODS: Postmortem dlPFC (BA9) tissue from 7 MDD and 8 well-matched controls was analyzed using 10x Genomics snRNA-seq and paired ATAC+RNA multiome sequencing. Sequencing data were processed with Cell Ranger pipelines, nuclei were filtered for quality and doublets/debris, and datasets were integrated and clustered using Seurat/Signac packages. Differential gene expression, chromatin accessibility, and transcription factor motif activity were tested between MDD and controls within each cell type, followed by peak-to-gene linkage and GO/KEGG and PsyGeNET enrichment to interpret dysregulated regulatory mechanisms.
RESULTS: A total of 20 distinct clusters encompassing major neuronal and non-neuronal populations were identified. Differential analyses uncovered extensive cell type-specific changes in chromatin accessibility and gene expression, particularly within excitatory layer 5/6 and inhibitory Pvalb neurons, as well as glial and vascular populations. Functional enrichment indicated dysregulation of synaptic organization, neurotransmission, myelination, stress-response, and immune-regulatory pathways across neuronal and non-neuronal cells. Notably, glucocorticoid-responsive transcription factors NR3C1/NR3C2 exhibited conserved regulatory networks implicating stress signaling in MDD pathophysiology.
CONCLUSIONS: Together, these findings provide a comprehensive single-nucleus atlas of gene regulation in the MDD PFC, highlighting coordinated dysfunction across neurons, glia, and vascular cells.
PMID:42630054 | DOI:10.1093/ijnp/pyag045
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